TWI344954B - Asymmetric hydrogenation process - Google Patents

Description

1344954 IX. Description of the invention: [Prior Art] 具有 (ρ 申请 申请 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有Medium. (〇)π

The desired stereoisomers There is a need for an efficient process for the preparation of such compounds containing mirror image isomerism. SUMMARY OF THE INVENTION The present invention provides a servant to the palm Dp receptor antagonist and its intermediates

The method is a "mirror-selective hydrogenation reaction of a metal-catalyzed reaction." [Embodiment] The present invention provides an asymmetric hydrogenation process for preparing a compound of the formula I or a salt thereof in an excess of at least 5% by% of the image isomer (4). 1

Wherein η is 1 or 2, R丨 is Η, Br or -S02CH3, and R2 is oxime, benzyl, 4-nitrobenzyl, 4-aminobenzyl, 4-trifluorodecylbenzyl or 4-chloro Benzyl. 100288.doc 1344954 The method comprises: treating the compound of formula II with a metal-to-palm ligand and a hydrogen donor

jaiL

Wherein when the hydrogen donor is H2, the process is carried out at a pressure of from about 0 to about 500 psig (pounds per square inch), and wherein the metal-to-palm ligand is (1) the 钌 axis To the palm phosphine ligand complex or (2) ruthenium ferrocene phosphine ligand complex or (3) 锗-TMBTP complex. a compound of formula I wherein R1 is -S02CH3 and R2 is 4-abenzyl or 4-trifluoromethylbenzyl, and a pharmaceutically acceptable salt thereof, is an antagonist of the DP receptor, and is useful for treating allergy Rhinitis, asthma, nicotinic acid-induced flushing, and other DP receptor-mediated disorders, disorders, and diseases. A compound of formula I wherein R1 is hydrazine, Br or R2 is hydrogen, benzyl, 4-nitrobenzyl or 4-aminobenzyl is an intermediate which can be subsequently converted to the desired DP antagonist. In a subset of the methods of the invention, the metal-to-palm ligand is a ruthenium phosphatidyl ligand complex. In one embodiment, the axial-to-palm coordination system is selected from the group consisting of BINAP, tol-BINAP, xyl-BINAP 'Synphos 'Solphos ' MeO-BIPHEP ' hexaPHEMP ' C(l-6)-tunaphos, P-Phos , xyl-P-Phos and TMBTP. In a second specific embodiment thereof, the metal-to-palm ligand is (p--hydrocarbon) Ru (axial to palm ligand)-X2, wherein X is as defined below; From BINAP ' tol-BINAP ' xyl-BINAP ' Synphos ' Solphos ' MeO-BIPHEP, hexaPHEMP, C(l-6)-tunaphos, P-Phos, 100288.doc 1344954 xyl-P-Phos and ΤΜΒΤΡ, and Halogen, for example, gas roots. In a second subset of the process of the invention, the metal-to-palm ligand is a ruthenium-iron phosphine ligand complex. In a specific embodiment thereof, the ferrocene group

Walphos, a TMBTP complex of formula (k). In the embodiment, the metal-to-palm ligand

The phosphine coordination system is selected from the group consisting of f-BlNAPHANE josiphos, and taniaph〇s of formula (I). In a third subset of the method of the invention, the metal-to-palm ligand is 铑_ is [(C〇D)Rh(TMBTP)]X, wherein χ is preferably a function root, for example, a gas radical β In a fourth subset of the process of the invention, the T.T^_hydrogenation reaction is carried out in the presence of a test and in the presence of a Group I or Group II salt, in the presence of a salt. The second subset of the second method provides a method for preparing at least 50% of the compound of the formula la (e) or a salt thereof,

Gas-treating the compound of formula Ila or comprising: a metal-to-palm ligand and a salt thereof

Wherein when the chlorine precursor is H2, the method is carried out at a pressure of from about 0 to about 100288.doc 1344954 psig (pounds per square inch), and wherein the metal-to-palm ligand is ( 1) 钌 axial 对 phosphine ligand complex or (2) 铑 掌 二 戊 戊 基 基 配 或 或 or (3) _ tmbTP complex.

In a specific embodiment thereof, the asymmetric hydrogenation reaction of compound Ila to compound la is carried out using a ruthenium axial phosphine ligand, wherein the coordination system is selected from the group consisting of BINAP, tol-BINAP, xyl-BINAP, Synphos, Solphos, 5_Cl, 6-MeO-BIPHEP, MeO-BIPHEP, hexaPHEMP, C(l-6)-tunaphos, P-Phos, xyl-P-Ph〇s and TMBTP. The metal-to-palm ligand is, for example, (p-halo-hydrocarbon) RU (axial to palm ligand)-X2, wherein X is as defined below; the pair of palm ligands is preferably 6 to eight卩, ratio 1-BINAP, xyl-BINAP, Synphos, Solphos, MeO-BIPHEP, hexaPHEMP, C(1-6)-tunaphos, P-Phos, xyl-P-Phos, and TMBTP, and X is a halide, for example, Chloride.

In a second specific embodiment thereof, the metal-to-palm ligand is a (1) fluorene-ferrocenyl-phosphine ligand, wherein the coordination system is selected from the group consisting of f-BINAPHANE, Walphos' (k) Josiphos, and taniaphos of formula (1); or (2) money-TMBTP complex. In a third embodiment thereof, it is from about 500 psig (eg, from about 0 to about 250 psig or from 0 to about 50 psig or from 0 to about 20 psig or from 0 to about 10 psig) The asymmetric hydrogenation reaction of the compound 11a to form the compound la using hydrogen is carried out under pressure; the metal-to-palm coordination system is selected from the group consisting of (1) having BINAP, tol-BINAP, xyl-BINAP, Synphos, Solphos, MeO-BIPHEP'钌aPHEMP, C(1-6)-tunaphos 'P-Phos, xyl-P-Phos and TMBTP ruthenium complex; (2) with f-BINAPHANE, 100288.doc 1344954 phos formula (k) josiphos, formula (1) ) a tantalum complex of taniaphos or TMBTP. The asymmetric hydrogenation reaction is preferably carried out in the presence of a base. • In the method of the present invention, the "metal-to-palm ligand" is an optically active ruthenium or osmium-phosphine complex which is pre-formed from a catalyst precursor and a palm ligand. The spot is formed by combining the catalyst precursor and the palm ligand. The metal-to-palm ligand is typically used in an amount of from about 1 to about 1 mole, preferably from about 2 to about 5 mole percent, for example, about 〇. • Suitable catalyst precursors include (but are not limited to) [Rh(L')X2]2, RUX3,

Ru(l,)(allyl)2, Rh(c〇D)2X, Rh_ outer χ, [Rh(c〇D)x]2 ' [Rh(NBD)x]2, [Rh(c〇 E) 2x]2, _(ethylene) 23⁄4 and [Rh(售)2X]2' where c〇D is M•cyclooctadiene, NBD is raw borneol, and COE is cyclooctene; ^, Br, j, trifluoromethanesulfonate, acetate, methanesulfonate, benzenesulfonate, I or B (Ar) 4 'and L' is an aromatic hydrocarbon (for example, benzene, toluene, hydrocarbons, Xylene, chlorobenzene, dichlorobenzene), nitrile (for example, acetonitrile), shouting (for example, tetrazole _ ° south, methyl third-butyl ether, diethyl ether), amine (for example, triethylamine, two Isopropylethylamine), a dilute (eg, ethylene, butene, cyclooctane, styrene, norbornene) or an allyl group (eg, methallyl). Examples of suitable preformed metal-to-palm ligands include, but are not limited to, (for palm ligands) RuX2, (palphali ligand) RUX2 (7), where Y is dimethylamine, triethylamine , dimethyl sulfoxide or acetone 'and X is as defined above. These on-demand precursors are well known in the art and are commercially available or can be made in accordance with procedures of known literature. "Axial-to-palm phosphine ligand" means an optically active diphosphine whose optical activity is 100288.doc 1344954 is produced by a confinement of a single chemical bond, M. Examples of the bromophosphine ligand include, but are not limited to, the ligands shown in the table, wherein Ar is, for example, phenyl, m- or p-tolyl, xylyl and methoxyphenyl; 2 is, for example, methyl, trimethyl or methoxy; Ra and Rb are independently fluorene, methyl, trifluoromethyl or methoxy, and Rc is hydrazine or phenyl. Some specific examples are ΒΙΝΑρ ( Formula (a), Ar=

Phenyl), tol-BINAP (formula (a), Ar=p-tolyl), χγ1·ΒΙΝΑΡ (formula (a), Ar=3,5-diphenylene), Η8-ΒΙΝΑΡ (formula (b) , Ar = phenyl), SYNPHOSTM (formula (c), Ar = phenyl), SEGPHOS (formula (d), Ar = phenyl), Solphos (formula (e), Ar = phenyl), diphenylene Solphos (formula (e),

Ar=3,5-diphenylene), MeO-BIPHEP (formula (f), Ar=phenyl, Z=methyl, Ra=Rb=Rc=H), hexaPHEMP (formula (f), Ar=benzene Base, Z = Ra = Rb = sulfhydryl, RC = H), tunaphos (formula (g), Ar = phenyl, and π is 1 to 6), ΤΜΒΤΡ (formula (h), Ar = phenyl), P =phos (formula (1) 'Ar=phenyl), tol-P-Phos (formula (1), Ar=nonylphenyl), xyU-Phos (formula (1)'

Ar = 3,5-dimethylphenyl). 100288.doc 10 - 1344954

" Ferrocenylphosphine ligand" including, but not limited to, the ligands shown in Table 2, that is, Walphos (formula (j), wherein each of Rd and Re is methyl or trifluoromethyl ), josiphos of formula (k), taniaphos of formula (1), and f-BINAPHANE (m). 100288.doc 1344954

Table 2

The metal-to-palm ligands suitable for use in the present invention are commercially available or can be known from the prior art by a catalyst precursor and a palm coordination system, and the process is described in In the reference examples below. The hydrogen donor can be hydrogen, formic acid or a salt thereof (e.g., sodium formate) or cyclohexane. It is preferred to produce hydrogen. The compound of formula II can be prepared by lightly referring to the procedure described in Example 2. The asymmetric argonization process can be included as needed, and can be inorganic or machine tested. formula! The salt of the formula η is formed by using these tests. The inorganic test is, for example, a group I or π group hydroxide, a burnt oxide, an aryl oxide, a burnt anion, an aryl anion, a quinone, and a quinone derived leaf release (handsome). The organic base includes, for example, 113,3. tetramethylphosphonium (TMG), 2,3,4,6,7,89 Μ octahydrotetrazol (Μ·小丫呼(卿), Μ•diazepine Egg '3 〇]壬5-ene (DBN), arginine, betaine, caffeine, choline 'μ,-dibenzyl I00288.doc -12- 1344954 ethylenediamine, diethylamine, 2_two Ethylaminoethanol, 2_di-T-aminoethanol, ethanolamine, ethylenediamine, hydrazine-ethylmorpholine, hydrazine-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine , isopropylamine, dicyclohexyl, lysine, phenethylamine, methyl-reducing glucosamine, morphine bottom, polyamine resin, procaine, guanidine, theobromine, three Ethylamine, trimethylamine 'tripropylamine, tris(hydroxymethyl)aminomethane, methylbenzylamine, 1>4-diazabicyclo[2 2.2]octane φ (DABC0), butylamine, dibutylamine , dimethylphenylamine, diisopropylamine, diisopropyl decylamine, traded sponge, dimethylaminopyridine, third butylamine, tri-n-butylene, diethanolamine, trimethyl 0 Than bite, sputum, N_methyl sputum, tetramethyl bottom bite. The asymmetric hydrogenation reaction may additionally comprise a salt selected from the group consisting of Group I or Group 11 compounds, trifluoromethanesulfonates, sulfonates, acetates, and borates. The asymmetric argonization reaction is carried out in an organic solvent with or without a cosolvent. Suitable organic solvents include alcohols such as, for example, methanol, ethanol, n-propanol, isopropanol, third-butanol; esters, for example, ethyl acetate and isopropyl acetate; guanamines, for example, Dimethylmethaneamine and dimethylacetamide; functionalized hydrocarbons such as 'dichlorodecane, dichloroethane, and dichlorobenzene; screaming' such as 'methyl tert-butyl ether and Tetrahydrofuran; ketones, for example, acetone and 2-butanone; aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as 'hexane and heptane; nitriles such as acetonitrile; and sulfoxides For example, dimethyl sulfoxide. The above solvents may be used singly or as a mixture of one or a combination of granules or water. In a particular embodiment, the asymmetric hydrogenation reaction is carried out in a base solvent (e.g., methanol). The reaction temperature may range from about -20 to about 120 t; preferably from about ambient temperature to about 7 ° C, and more preferably from about 4 Torr to about 6 (rc. The reaction is usually in (d) The hourly reaction time is usually from about 3 hours to about 24 hours. When the asymmetric hydrogenation reaction is carried out using hydrogen, the pressure is from about to about 500 psig; in a specific embodiment The pressure is from about 250 to about 250 psig; in the second embodiment, the pressure is from about 〇 to about 15 〇 - pSlg '. In a third embodiment, the pressure is from about 〇 to About 5 〇 φ PSlg, in the fourth embodiment, the pressure is from about 〇 to about 20 psig; and in the fifth embodiment, the pressure is from about 〇 to about 1 〇 psig. The selectivity is inversely proportional to the private pressure; therefore, increasing the hydrogen pressure generally results in a decrease in the mirror image isomerism selectivity, and a H2 pressure above about 5 psig results in a product mixture containing less than 5% ee. Without being bound by theory, the inventors hypothesized that the compound (E-different to the double bond outside the ring) The corresponding inward-isomeric substance can be produced by transition metal catalytic isomerization by a dish cyclopentene compound. The intrinsic-isomer is a hydrogenation which produces a product of the image-rich isomerization of formula I. Substrate. Under low pressure, the isomerization of the E-isomer forms the inward-isomerization faster than the hydrogenation of the exocyclic double bond. Thus, in another embodiment of the method of the invention The hydrogenation reaction is carried out at a pressure of from 0 to about 20 psig; preferably from about 1 to about 1 psig. Another aspect of the invention provides a method of preparing a compound of formula I or a salt thereof of at least 50% ee. The invention comprises the treatment of a hydrazine compound or a salt thereof by hydrogen at a pressure of from about 0 to about 20 psi in the presence of a ruthenium-to-palm ligand complex or a ruthenium-to-palm ligand complex, and a base. A hydrazine compound or a salt thereof or a mixture thereof of 100288.doc -14· 1344954.

In this case, when a low pressure asymmetric hydrogenation reaction is carried out, the pressure is preferably from 0 to about 10 psi, and all other reaction conditions are as described above. Reference Example 1 Preparation of Compound (13) (1)

CIS03H, S02Cf2 60°C, 3 hr (4)

NaOH F-

ONa Na OMe + (C〇2Et)2--e〇hp 20-25°C

OMe/OEt HCOCOgNa 丨 H20, K2HP〇4 pH9.4-6.5

S02CI

,so2ch3 BrCH2C02H H20, 90°C, 10h

NHNH2 ΗΟΙ,δΟΐ; .CH, S02CH3 .S02CH3 - -NH-N=a TBAl, THF, 50°C, 5h p-CI-C6H4CH2CI, NaOH(5N)

NaHC03 NaS03 " H20, 30°C, 2h

CH3C(0)CH3 (11)

CH 3

MeS03H, MTBE N-NH3+ -SOaCHgso2chS^||(12) 100288.doc •15- 1344954

Step 1. Preparation of (2E)-(2-oxocyclopentylene)acetic acid (Compound 3) Toluene (12.5 ml per gram of cyclopentanone), cyclopentanone (1 equivalent) and diethyl oxalate (1) Equivalent) was charged into a round bottom flask. At 2〇. The hydrazine was stirred under nitrogen for a period of one hour, and sodium methoxide (30% by weight in methanol, 1 equivalent) was added by a funnel. The resulting slurry was allowed to warm to 451 and aged for an hour. The slurry was allowed to cool to 15 to 2 Torr and aged for one hour. The slurry was filtered and the cake was washed with toluene (7.5 ml per gram of cyclopentane). The filter cake was washed with toluene (7.5 ml per gram of cyclopentanone) and dried in a stream of nitrogen for one hour, then dried under vacuum at 451 overnight to give a methyl ester of br. Compound (2) of a mixture of base esters. Glyoxylic acid (50% by weight aqueous solution, 丨.28 equivalent) was placed in a round bottom flask. Water (3.17 ml of aqueous glyoxylate per ml) was added and the solution was allowed to cool to 5 °C. 5N sodium hydroxide (128 equivalents) was slowly added over about one hour to maintain the reaction temperature below 10 °C. The yang is monitored during the addition. Adjust the final pH to 45 (+ / 〇 ... so that the formed sodium thioate solution is cold - to _2 ° C ° at room temperature, compound (2) (one equivalent) and deionized water (mother Compound (2) 1 liter) was placed in an individual container. The solution was cooled to 1 ° C. At 10 C, dibasic potassium phosphate (1.75 equivalents) was added to the solution 100288.doc -16 - 1344954 The resulting turbid solution was cooled to _3 ° C, and a sodium acetate solution was added thereto at -3 (by: about 30 minutes). After the addition, the batch was aged at _3 to 0 ° C. One hour. The batch was allowed to heat to 1 Torr, and methyl third-butyl ether (MTBE, 526 ml per mole of compound (2)) was added. Phosphoric acid (85%, 2.65 eq.) was added to adjust the pH to 3.0 (+/- 0.1) The phases were thoroughly mixed and took 30 minutes and allowed to separate. The lower aqueous layer was extracted with MTBE (405 ml per mole of compound (2)), and the MTBE layers were combined. The MTBE layer was washed twice with a 5% brine solution and &quot;as it was." Step 2· Preparation of Compound (12) Under a nitrogen atmosphere, gas sulfonic acid (3 equivalents) Sub-branched chlorine (1·5 equivalent) was placed in a round bottom flask. The solution was heated to a temperature of +5 5 to +60 ° C and 1,4-difluorobenzene (1 equivalent) was added dropwise over 2 hours. After completion of the addition, the reaction mixture was further aged at +60 C for one hour and allowed to cool to room temperature. The batch was added to the decyl-tert-butyl ether (per mole) for one hour. 1 liter of difluorobenzene) and a cold (+5 °c) biphasic solution of water (1 liter per mole of difluorobenzene). Separate each layer 'with water (1 liter per mole of difluorobenzene, two (2) Washing the organic layer. Prepare sodium sulfite (one equivalent) and sodium bicarbonate (2 equivalents) in water (per m-difluorobenzene solution in a separate container. Add the compound in one hour at about +25 〇 CT (5) The MTBE layer is added to the solution at the same time, and the mixture is simultaneously mixed. The two-phase solution is allowed to mix and take 'one hour' and the layers are separated. The compound (6) is used as it is in the next step. Aqueous solution. Add sodium hydroxide (50% '1.2 equivalents), and bromoacetic acid (1.2 bases) to the 100288.doc -17· 1344954 water containing compound (6) In the solution, the reaction mixture (pH~8.2 〇) was heated to still +90 C, aged for 10 hours, and allowed to cool to room temperature to crystallize the product, which was filtered and passed through water (per mole of difluoro Phenylhydrazine. 5 liters) was washed and dried under vacuum at <30 to 40 ° C (melting point ~60 ° C) to give compound (7). ^ N-methylpyrrolidone (NMP, per mole compound ( 7) 8 〇〇 ml)'. Compound (7) (one equivalent), and hydrazine (35% aqueous solution, 2.5 equivalents) were placed in a round Teflon flask. The solution was heated to a high of 9 Torr &lt;t, and φ was aged under nitrogen for 6 hours. The reaction mixture was then cooled to room temperature and acetone (2 eq.) was slowly added (~1 hr). After the addition of acetone, the ruthenium begins to crystallize. After aging at room temperature for one hour, water (hours per liter of compound (7) 1.5 liters) was added. The mixture was aged for one hour, filtered, and washed twice with water, then dried at EtOAc (EtOAc) to afford compound (11). THF (1 liters per mole of compound (11) ), compound (11) (prepared), tetrabutylammonium iodide (0.03 equivalent), 4-gas benzyl gas (1.05 • equivalent), and 5N NaOH (5 equivalents) were charged into the reaction vessel. The biphasic mixture was heated to 50 ° C and stirred for 5 hours. The mixture was then cooled to room temperature and the aqueous layer was separated. The organic layer was washed with a 15% aqueous NaCI solution (1 liter per mole of compound (11)). The organic mixture was heated to still 50 C, and methanesulfonic acid (MSA, 1 丨 equivalent) was added over 0.5 hours. After the addition was completed, 0.1 weight of salt seed crystals were added to initiate the crystallization reaction. The batch mixture was aged for 2 hours and then MTBE (4 liters per mole of compound (1)) was added in one hour. After a further 2 hours at (10), the batch was allowed to cool to room temperature and aged for 2 hours. The mixture was passed through 100288.doc -18·1344954 and the filter cake was washed twice with MTBE and then dried under vacuum to give the hydrazine/MSA salt (compound (12)).

Step 3. Process for the preparation of the compound (13) A to a solution of the compound (3) in MTBE (0.813 M in MTBE, 1 to 1 equivalent) to the compound (12) (one equivalent) of acetonitrile Each mole of compound (12) 3.4 liters in the slurry. The formed slurry was degassed and heated to between +50 and 55 C between φ, which took 24 hours. At +50. (: Add water (340 ml per mole of compound (12))' and cool the reaction mixture to room temperature. Subtract the mixture and pass 90/10 acetonitrile/water (per mole compound (12) 85 ml) and methanol (1.7 liters per mole of compound (12)). Clean it at +4〇 to 5〇

The filter cake was dried in an oven and took 24 hours to obtain the product. Method B Compound (12) (-equivalent) and compound (3) diisopropylamine (DIPA) salt (equivalent) and propionic acid (repair per mole compound (12) at 20 to 25 ° C 3.3 3 liters) was placed in a round bottom flask. The slurry was allowed to warm to and aging for 3 hours. Methanesulfonic acid (1.2 equivalents) was added over 3 to 5 minutes. The slurry was aged for one hour at 5 to 6 ° C, cooled to 30, and water was added for about $ minutes (0.33 liter per mole of compound (12)). The slurry was aged for 3 minutes and filtered. The light yellow filter cake was washed with 10 Torr/hydrous methanol (1% water, 90% methanol, 2 liters per liter (12)) until the filtrate was colorless. The filter cake was washed with ethanol (mole molar compound (12) 1 liter). The cake was dried in a stream of air' and then dried in a vacuum oven at 40 ° C to give the product. I00288.doc -19- 1344954 Preparation of Compound (13) TMG Salt: Add 1,1,3,3·tetramethylguanidine (TMG, 99%, 24.5 ml, 193 mmol) at 23 °C Compound (13) (70 g, 161 mmol) of isopropylacetamide (IPAc '280 mL) and MeOH (140 mL) was then taken and then dissolved. Additional IPAc (125 mL) was added as a seed which resulted in the formation of a slurry. Additional IPAc (125 mL) was added and the mixture was aged overnight. The slurry was subjected to distillation in a constant volume by simultaneous addition of IPAc. When the supernatant liquid reached 5 mg/ml, the distillation was interrupted and the slurry was cooled in an ice bath. The crystals were filtered, and dried by ice-cold IPAc washing to give 85.6 g of a crystalline solid, which had a purity of 96.8 wt. Preparation of Compound (13) DBU Salt: DBU (99%, 0.21 mL, 1.36 mmol) was added to compound (13) (0.50 g, 1.2 mmol) MeOH (3 mL). Inside, the solution, which is now homogeneous, is cooled to 23 ° C 'and serves as a seed to cause the formation of a slurry. MTBE (6 mL) was added and the slurry was aged overnight. The solid was filtered and washed with 4:1 MTBE/MeOH. The solids were dried to give 〇57 g of compound (13) DBU salt. Preparation of Compound (13) DBN Salt: DBN (98 ° / 〇, 0.33 mL, 2.65 mmol) was added to Compound (13) (1. gram, 2.30 mmol) of MeOH at 60 ° C ( 5 ml) in the body. The solution, which is now homogeneous, is then cooled to 23. (: Slowly add MTBE (4 ml) to induce crystallization on a regular basis. The resulting slurry was aged for 6 minutes. Additional MTBE (11 ml) was added to the slurry and further aged. Filter the solids, Washing with 5:1 MTBE/MeOH. Drying the solid 100288.doc -20- 1344954 to give 0.98 g of compound (13) DBN salt. Compound (13) Potassium salt: KOtBu (at 23 ° C) 95%, 285 mg, 2.41 mmol.) Compound (13) (1.00 g, 2.30 mmol) in MeOH (5 mL) was added. Slowly slowly added MTBE (5 mL) to the solution and The turbid solution was formed by filtration through a 0.45 micron syringe filter. Additional MTBE was added to the filtrate to cause the formation of a slurry. The slurry was aged for 60 minutes. The solids were filtered, followed by φ 5: 1 MTBE/MeOH, and 100 % MTBE washing. Drying the solids yielded 0.58 g of compound (13) potassium salt. Reference Example 2 Method for forming a catalyst in the field 脱In a glove box of inert atmosphere, degassed methanol (75 ml) was charged with [( Pair-paid hydrocarbons) RuC12]2 (0.369 grams, 0.60 millimoles) and (8)·BINAp (0.770 , 1.24 mmol) in a round bottom flask. Add degassed toluene (25 mL) and transfer the orange uneven solution to a ampule with a resealable Kontes adapter. The ampule is sealed, removed from the glove box, and heated at 50 to 60 ° C for 1 to 2 hours while stirring. The orange solution is placed in a glove box and stored at room temperature as a The molar concentration of the stock solution ([(----)-------------

Rh(COD)2BF2 and the desired round ligand in the flask (! · i molar equivalent L/Rh). The solution was stirred at room temperature for one hour. [Battery] = 0.016 Μ. The following non-limiting examples are provided to further illustrate the invention. 100288.doc 21 1344954 Example 1 [(3R)-4-(4-heteroyl)methyl-7-fluoro-5-(indenyl)-,,,,,,,,,,,,,,,,, b] ind-3-yl]acetic acid, TMG and DIPA salts

TMG salt Method A. Compound (13) (3.0 g, 6.9 mmol), ?(〇11) (23 ml), and a stir bar were placed in a reaction vessel. The tan slurry was stirred and TMG (0.8 mL, 6.9 mmol) was added via syringe. The resulting purple/brown slurry was degassed (vacuum/nitrogen x5) and the container was placed in the glove phase. The catalyst ([__BINAP) RuC12]2 (8.1 ml, in methanol/toluene (3:1) 〇 M 12M, j 4 mol/.) was charged by syringe. The trough is sealed, removed from the glove box, and connected to a hydrogen/nitrogen/vacuum manifold. After degassing the lead 1 to the pressure vessel line (vacuum/nitrogen X5), the stirred solution in the pressure vessel is degassed (nitrogen/vacuum χ3) and pressurized with hydrogen (hydrogen 40 psig/vacuum χ3). Wash and do not need to be stirred. The reaction solution was then placed under hydrogen (10 Psig), stirred, and warmed to 45-50 °C. After aging overnight (~15 hours), the formed homogeneous solution was allowed to cool to room temperature, and the pressure vessel was discharged to normal pressure. Ee=9i%. Method B. In the glove box, compound (13) TMC} salt (25 g, 4 6 mmol), degassed Me〇H (25 ml), [(p-supplied hydrocarbon) (s_ 100288. Doc -22- 1344954 BINAP)RUC12]2 (1.9 ml, 0·023 mm, 〇5 mol%), and a blending rod into a reaction pressure vessel, sealed the container, removed from the glove box, ^ and Connect to a hydrogen/nitrogen/vacuum manifold. After degassing the line leading to the pressure vessel (vacuum/nitrogen gas 5), the pressure vessel was degassed (nitrogen/vacuum x5) c&gt; the vessel was heated to 53 ° C, and subjected to hydrogen (hydrogen/vacuum x 3) pressure. Wash and then place it under hydrogen (10 Psig). The stirred slurry was aged overnight (~15 hours), then cooled to room temperature, and the pressure vessel was discharged to atmospheric pressure. • ee=91%. DIPA salt A slurry containing compound (13) (1.0 equivalent) and EtOH (1 liter per mole of compound (13)) was degassed by nitrogen sparging. The slurry was placed in an autoclave together with degassed Et3N (1.0 eq.) and degassed Et 〇H (0.5 liter per mole of compound (13)) by vacuum overnight. The pre-degassed 45% KOH (-equivalent) and degassed EtOH (100 ml) as a washing liquid were charged into the autoclave by a two-tank apparatus (5 liters and 15 liters). Pre-degassed EtOH (100 mL) from a separate Schlenk flask was then loaded by the same line (which was used to charge the catalyst). The EtOH feed must completely remove any KOH from the feed line that would harm the catalyst. The mixture can be degassed by a nitrogen-vacuum scrubbing process and passed through a two-container unit (2 liters and 15 liters of milliliters), followed by a 0.012 M S-BINAPRuC12-p--hydrocarbon complex 3 : i EtOH-nonylbenzene (0.5 mol%) and EtOH (100 ml) washing solution were placed in an autoclave. The mixture was degassed by washing three times with nitrogen pressure at 28-27 ° C and washing with hydrogen pressure three times. The mixture was then hydrogenated at 2 ° psig at 2 ° psig until the reaction was deemed complete (HPLC: &lt; 〇 1A% compound 100288.doc •23·(13) residue). The crude hydrogenation feed stream (164 mg/dm.) was placed in a SJ bottom flask. Let the 磬 接 ^ ^ ^ 丄 6 6 alcohol (mother free ether 2.9 liters). , + plus DIPA (2 equivalents). The solution was allowed to warm to 55 〇c. Propionic acid (2 equivalents) was added at about 5 C at about 5 hours. Aging the polymer under hunger,

The time-hours were cooled to (10) in one hour and aged-hours. The filter cake was washed with a &lt;&quot;lurry and washed with cold (5 c) ethanol (174 liters per mole of free acid) and acetic acid vinegar (L45 liters per mole of free acid). The cake was dried in a stream of N2 for one hour and at 35-45. Dry under vacuum. Example 2 Hydrogenation procedure using a ruthenium catalyst:

Transfer the rhodium catalyst solution (in methanol to 〇. 16M) to a pressure vessel containing the decyl alcohol solution of compound (13) and base (eg, TMG) in an inert atmosphere glove box. The container is sealed, removed from the glove box, and connected to a hydrogen/nitrogen/vacuum manifold. After the line leading to the pressure vessel was degassed (vacuum/nitrogen x5), the pressure vessel was degassed (nitrogen/vacuum X5). The vessel was subjected to a hydrogen (hydrogen/vacuum X3) pressure wash and placed under hydrogen (90 psig). The stirred slurry was aged overnight (~15 hours), and the pressure vessel was discharged at atmospheric pressure and then analyzed. Example 3

The catalyst was prepared using the procedure of Reference Example 2; use Example 1 'Method A 100288.doc • 24· 1344954

The procedure is hydrogenated. L (paid hydrocarbon) RuC12% concentration %ee BINAP 100 90 Solphos 92 -8 8 Diphenyl phenyl Solphos 100 -89 Synphos 96 89 TMBTP 100 -70 (R)-HexaPHEMP 100 -88 (S)-C6-TunaPhos 100 85 Reaction conditions: 1.2 mol. / 〇 catalyst, 50 ° C, 15 hours, milligrams of compound (13) / 1 ml Me 〇 H 〇 Know this 0 / μ 炎 匕 know s % ee is negative, so that psig, 100 use the touch The relative image isomer of the medium can give the desired product. Example 4 The method for converting the TMG salt of the compound of Example 1 into a free acid

The crude hydrogenation solution (105.5 grams) containing 10 grams of the product of Example 1 product (95 3/47 ratio of the mirror image isomer, thus to 9.53 grams of optically pure product analyte) was concentrated and converted to Ethyl acetate (Ac〇Et) was applied several times to ensure that no residual MeOH/indene/water remained. The volume was adjusted to 12 ml AcOEt (120 ml) per gram of TMG salt. Add water (relative to 1 _25 V®/.: 1 _5 ml). Heat the slurry to a maximum of +55, which takes about 10 hours. The slurry was allowed to cool to room temperature' and aged for an hour and then filtered. The filter cake was rinsed with recycled mother liquor and finally washed with AcOEt (35 mL). Drying at +40 ° C in an oven gave 9.0 g of TMG salt with ee of -98.5% (8.9 g of optically pure TGM salt analyte; about 93% yield). 100288.doc -25· 1344954 The dry cake (9 g; 7.1 g of free acid) was slurried in AcOEt (90 ml) and washed with 0.5 N aqueous HCl (90 mL) to become two Uniform layer. The layers were separated and washed with water (2 x 75 mL). The AcOEt solution formed was treated with Ec〇sorb C-941 (10% by weight loading relative to free acid, 710 mg). The slurry was aged for one hour at room temperature and filtered through a solka floe filter aid (with AcOEt wash). The colorless solution formed was concentrated and the volume of AcOEt was adjusted to 28.4 ml, and then water (142 μl to obtain KF to 5000) was added. The batch was heated to a temperature of +55 to 60 ° C to dissolve it. n-Heptane (about 8 ml) was slowly added to crystallize. The batch was aged at about 5 ° C for about one hour and the remaining n-heptane (105 6 ml) was added at +55 for 1 to 2 hours, allowed to age for a few hours' and allowed to cool to It was filtered at room temperature, washed with 80/20 n-heptane/AcOEt (~50 ml), and then dried in an oven for 24 hours at +4 liters to give about 6.6 g of free acid and "~99" - 7% of the product. Example 1 Method for Conversion of Compound DIPA Salt to Free Acid The slurry of Example 1 compound DIPA salt dry cake (9 g) in AcOEt (90 ml) was washed with 0.5 N aqueous HCl (90 liters). Two uniform layers. Separate each layer and wash the organic phase with water (2 x 75 mL). Treated with Ecos 〇rb c-941 (10% by weight loading relative to free acid, 71 〇 mg). The solution was aged for one hour under the 'fox, and filtered by s〇lka floe filter aid (+Ac〇Et washing solution), concentrated to form a colorless solution, and the volume of Ac〇Ht was made into 28.4. ML, and add water (142 μl to get ~5 〇〇〇KF). Heat the 忒 batch mixture to a height of +55 to 6 〇 (&gt;c Let it dissolve. Slowly add n-heptane (about 8 ml) to obtain. At +55. The batch is aged 100288.doc • 26 - 1344954 for about one hour, and at +55 for 1 to 2 Hour n ^ Listen to add the remaining n-heptane. Soar), aging for a few hours, and allow it to cool to room temperature. Filter the slurry and pass the / ' / 20 of the positive - Gengyuan / AcOEt (~ 50 ml Washing. On +40 t: &quot;7^ 9 Η Η. Drying the solid in the head, taking 24 hours, get 6.9 grams of desired product. 100288.doc -27-

Claims (1)

1344954 f Patent Application No. 094,109,815 Chinese Patent Application Serial No. (10, Patent Application Range: 1. A method for the asymmetric hydrogenation of a compound of the formula I or a salt thereof in an excess of at least 50% of the image isomer excess (ee). Wherein η is 1 or 2, R1 is Br or -S02CH3, and R2 is hydrazine, benzyl, 4-nitrobenzyl, 4-aminobenzyl, 4-trifluorodecylbenzyl or 4-chlorobenzyl, The method comprises: treating a compound of formula II or a salt thereof with a metal-to-palm ligand and a hydrogen donor Wherein when the hydrogen donor is ruthenium 2, the process is carried out at a pressure of from about 0 to about 500 psig (pounds per square inch), and wherein the metal to palm ligand is (1) 钌 axial a palladium phosphine ligand complex or (2) a ruthenium ferrocene phosphine ligand complex or a (3) 锗-TMBTP complex. 2. The method of claim 1, wherein the metal-to-palm ligand is a ruthenium-antimony-phosphine ligand complex, and the palm-coordination system is selected from BINAP (formula (a), Ar=phenyl ), tol-BINAP (formula (a), Ar=p-phenylene), xyl-100288-1000211.doc 1344954 BINAP (formula (a), Ar=3,5-diphenyl), Synphos (c), Ar = phenyl), Solphos (formula (e), Ar = phenyl), MeO-BIPHEP (formula (f), Ar = phenyl, Z = methyl, Ra = Rb = Rc = H) , hexaPHEMP (formula (f), Ar = phenyl, Z = Ra = Rb = methyl, RC = H), C (l-6) - tunaphos (formula (g), Ar = phenyl, and n is 1 To 6), P-Phos (formula (i), Ar = phenyl), xyl-P-Phos (formula (i), Ar = 3,5-diphenyl) and TMBTP (formula (h), Ar = stupid base), 3. The method of claim 1, wherein the metal-to-palm ligand is (p--hydrocarbon) Ru(S)-BINAP-C12, wherein BINAP is formula (a), And Ar = phenyl, 4. The method of claim 1, wherein the metal-to-palm ligand is (for palm ligand) RuX2, wherein X is independently selected from the group consisting of α, Br, I, trifluorosulfonate , acetate, mesylate, sulfonate, BF4, and B(Ar)4, and Ar is phenyl, m- or p-tolyl, diphenylene and methoxyphenyl. 5. The method of claim 1, wherein the metal-to-palm ligand is a ruthenium-ferrocenyl phosphine ligand complex, and the ferrocenyl phosphine coordination system is selected from the group consisting of f- of formula (m) BINAPHANE, Walphos of formula (j), wherein ... and !^ each are fluorenyl or trifluoromethyl, josiphos of formula (k), and taniaphos of formula (1), 100288-1000211.doc 6. As requested, compound The method of claim 1, wherein the metal-to-palm ligand is 铑-TMBTP ' wherein TMBTP is formula (h), and Ar = phenyl, as in the method of claim 1, wherein the hydrogenation reaction is in the presence of a base and It is carried out in the presence of a Group I or π group salt. A method for asymmetric hydrogenation of a compound of formula la or a salt thereof having at least 50% of an image isomer excess (ee) Its package, · metal-to-palm stereo and hydrogen donor treatment of Ila compounds or their salts When Zhongtian's gas is H2, the method is carried out at a pressure from about to about 500 psig (per square inch of gauge pressure), and wherein the metal-to-palm ligand is (1) 钌 axial pair a palm phosphine ligand complex or (2) a ruthenium ferrocene-based rib ligand complex or a (3) 锗-TMBTP complex. The method of claim 8 wherein the hydrogenation reaction is carried out in the presence of 100288-1000211.doc 13449.54 with hydrogen, and wherein the metal-to-palm coordination system is selected from the group consisting of (1) having BINAP (formula (a), Ar = phenyl), tol-BINAP (formula (a), Ar = p-nonylphenyl), xyl-BINAP (formula (a), Ar = 3,5-diphenyl), Synphos (formula (c) ), Ar = phenyl), Solphos (formula (e), Ar = phenyl), MeO-BIPHEP (formula (f), Ar = phenyl, Z = methyl, Ra = Rb = Rc = H), hexaPHEMP (Formula (f), Ar = phenyl 'Z = Ra = Rb = sulfhydryl, Re = H), C(l-6)-tunaphos (formula (g), Ar=phenyl, and n is 1 to 6), P-Phos (formula (i) 'Ar=phenyl), xyl-P-Phos (formula i) a ruthenium complex of Ar = 3,5-dimethylphenyl) or TMBTP (formula (h), Ar = phenyl), Rb 100288-1000211.doc 1344954 (2) having f-BINAPHANE (formula (m)), Walphos (formula (j), wherein each of Rd&amp; Re is a mercapto or trifluoromethyl), josiphos of formula (k), taniaphos of formula (1) Money complex PAr2 PAr2 or TMBTP (formula (h), Ar = phenyl), . 10. The method of claim 8, wherein the hydrogenating reaction is carried out at a pressure of from about Torr to about 20 psig. 11. A compound of formula II or a salt thereof: 100288-1000211.doc -6- 1344954 Where η, R1 and R2 are as defined in claim 1. Wherein η is 1 and R1 is 12. The compound of claim 1 or a salt thereof, -S02CH3, and R2 is 4-chlorobenzyl. 100288-1000211.doc